200301108 A7 --- B7 五、發明説明（1 ) 發明技術領域 本發明係關於氮咀衍生物之安定調製物。 (請先閱讀背面之注意事項再填寫本頁) 丰艮據本發明在醫藥組成物中使用的氮咀衍生物可以用 下列通式（la)或（ib)表示：200301108 A7 --- B7 V. Description of the Invention (1) Technical Field of the Invention The present invention relates to a stable preparation of a nitrogen nozzle derivative. (Please read the notes on the back before filling this page) The nitrogen nozzle derivative used by Fenggen in the pharmaceutical composition according to the present invention can be represented by the following general formula (la) or (ib):
、CN、（C1-C4)烷氧基或0H基取代之芳族或雜芳族基。 在上述氮咀衍生物之定義中，芳基係指特別是苯基或 萘基’雜芳基是吡啶基、呋喃基、噻嗯基、噻唑基、咪唑 基或噚〇坐基’且鹵基是氟、氯、溴或碘。 先前技術 經濟部智慧財產苟員工消費合作社印製 在專利申請案 WO 00/1 5609、WO 0 1/64633、WO 00/64634及WO 99/0 145 1中，曾經揭示通式（la)或（lb)之氮 咀衍生物及其應用，具體地說，這些氮咀衍生物特別有用 ’因爲其對於***酚受體且特別是CB1-型受體有高親和力 〇 不巧地，氮阻衍生物之產物只有非常輕微的水溶性， 直到現在，面對用藥通式（la)或（lb)之氮咀衍生物，特別是 經由口服途徑在含尤其是纖維素、乳糖及其他賦形劑之片 本紙適用中國國家標準（CNS ) A4規格（210X297公缝Ί 一 200301108 A7 B7 五、發明説明（2 ) 劑調製物形式，但是此種調製物不都是足夠合適於這些幾 乎不是水溶性的產物，因爲生物利用度過低。 (請先閱讀背面之注意事項再填寫本頁) 許多文獻揭示合適將疏水性活性成份溶解及/或加強生 物利用度之系統，但是，測試的系統至今證明無效用於製 備含上述定義的氮阻衍生物之醫藥組成物，其係安定且可 生物利用且其中氮咀衍生物是在有效濃度下溶解。 具體地說，J. Pharm Sciences，89(8)，967 (2000)及 Pharmaceutical Technology Europe, ρ· 20，S etember 2000 提 到幾乎不溶於水的活性成份在中等鏈甘油三酯之調製物， 但是用以Miglyol ®爲基質之調製物進行的試驗從其生物力 用度之觀點得到機能不足的結果。 經濟部智慈財產苟員工消費合作社印製 而且，國際專利申請案WO 95/24893揭示含用於調製 疏水性活性成份及用於強化其生物利用度之可消化的油、 親脂性表面活性劑及親水性表面活性劑之組成物，不巧地 ，上述氮咀衍生物經證明此種調製物之生物利用度太微弱 ，具體地說，此種氮咀衍生物之調製物在Miglyol ® /Caprylol ©/Cremophor ®系統從藥物動力學之觀點也證明 在活體內機能不足。 發明內容 現經發現且其構成本發明之主題，可以製備化學及物 理安定的醫藥組成物，其中含通式（la)或（lb)之衍生物，視 需要結合另一種可加強通式（la)或（lb)之氮咀衍生物效應之 活性成份，系統中含至多2種主要賦形劑選自具有親水性 本纸張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 200301108 A7 B7 五、發明説明（3 ) (請先閱讀背面之注意事項再填寫本頁) 特徵可溶解通式（la)或（lb)之氮坦衍生物之非離子性表面活 性劑，且視需要選用可加強氮咀衍生物效應且可造成膠體 系統形成之活性成份，視需要補充親脂性本質可安定調製 物之第二種賦形劑。 根據本發明，較佳的組成物含： •至少一種通式（la)或（lb)之活性成份， •視需要結合另一種可加強通式（la)或（lb)之氮咀衍生 物效應之活性成份， •具有親水性特徵可溶解通式（la)或（lb)之氮咀衍生物 之非離子性表面活性劑，及視需要選用可加強氮咀衍生物 效應且可造成膠體系統形成之活性成份， •視需要選用具有親脂性特徵且HBL低於10並能安 定組成物之表面活性劑， •視需要選用額外添加劑，其係選自安定劑、防腐劑 、可以調節黏度之藥劑、可以改良例如特殊感覺性質之藥 經濟部智慧財產局員工消費合作社印製 根據本發明，具有親水性特徵可溶解通式（la)或（lb)之 氮阻衍生物之非離子性表面活性劑，及視需要選用可加強 氮咀衍生物效應且可造成膠體系統形成之活性成份，可以 選自在低溫（T°C <60 °C )熔化之固體或半固體藥劑，或選自 HLB介於1 〇及2〇之液體藥劑，例如聚乙二醇與飽和的脂 肪酸之甘油酯。 當然在上述定義中，飽和的脂肪酸可含從6至1 8個碳 原子’且聚乙二醇（PEG)與飽和的脂肪酸之該甘油酯可以得 本纸張尺度適用中國國家標準（CNS ) A4規格（2U)X 297公爱） -8 - 200301108 A7 _ B7 五、發明説明（4 ) 自天然或合成。 (請先閱讀背面之注意事項再填寫本頁) 舉例而言，具有親水性特徵之非離子性表面活性劑可 以選自藥劑例如Labrasol ® [辛醯己醯macrogol-8甘油酯] 及 Gelucire ® 產品：Gelucire 44/14、Gelucire 50/13 [月桂 醯基（或硬脂醯基、棕櫚醯基）macrogol-32甘油酯]。 根據本發明之較佳具體實施例，該組成物也可含具有 親脂性特徵且HBL低於10並能安定組成物之表面活性劑 ，此藥劑可以選自可加強通式（la)或（lb)之氮咀衍生物及視 需要相關的活性成份之溶解度之藥劑，根據本發明此藥劑 可以選自聚乙二醇與脂肪酸特別是不飽和的脂肪酸之甘油 酯，選自聚乙二醇與脂肪酸之酯類或脂肪酸與山梨糖醇之 酯類，當然上述脂肪酸可含從6至1 8個碳原子。 舉例而言，該藥劑可以選自油酸、Labrafil ®產品[油 醯基（或亞麻油醯基）macrogol-8甘油酯]例如 Labrafil M1 944CS、Caprylol ® (聚乙二醇單辛酸酯）或 Span20 ® (山梨糖醇單月桂酸酯），列出之本名單沒有限制. 在上述賦形劑中，Labrasol ®、Gelucire ®或 Labrafil ®/Labrasol ®對尤其更特別較佳。 經濟部智慈財產局Μ工消費合作社印製 也經證明（但是在本申請案提出前尙未公告）對於部份治 療例如肥胖症，有利於在用藥通式（la)或（lb)之氮阻衍生物 時同時用藥西布特胺（s ib u tr a m丨n e) ’其在減少食物消耗時造 成協同效應。 西布特胺及其效應經揭示在下列文獻：W0 90/061 1 10; D. H. RYAN et al., Obesity Research, 3 (4), 5 53 ( 1 995); H. 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0x 297公釐） 200301108 A7 B7 五、發明説明（5 ) (請先閲讀背面之注意事項再填寫本頁) C. JACKSON et al., British Journal of Pharmacology, 121, 1 758 (1 997); G. FANGHANEL et al., Inter. J· Obes·，24 (2)， 144 (2000); G. A. BRAY et al.，Obes. Res.，7 (2)，189 ( 1 999). 而且，對於其他治療例如例如精神***症或神經障礙 例如巴金森氏症之治療，有利於在用藥通式〇a)或（lb)之氮 咀衍生物時同時用藥一或多種可活化腦中多巴胺能神經傳 遞之藥劑，這些組合物可以加強多巴胺能單獨治療之效應（ 左旋多巴、多巴胺能刺激劑及酵素之抑制劑），並可減低副 作用尤其是運動困難。 在多巴胺能刺激劑中，可以具體舉例之產品如下：溴 隱亭（Novartis)、卡柏格林（cabergoline) (Pharmacia Corp.) 、亞德格立（adrogolide) (Abbott Laboratories)、BAM-1 1 1 0 (Maruko Seiyaku Co Ltd)、Duodopa ® (Neopharma)、L-多 巴、多巴多（dopadose) (Neopharma)、CHF1512 (Chiesi)、 NeuroCell-PD (Diacrin Inc)、 PNU-95666 (Pharmacia & 經濟部智慧財產局員工消費合作社印製, CN, (C1-C4) alkoxy or OH-substituted aromatic or heteroaromatic groups. In the above definition of a nitrogen nozzle derivative, aryl means especially phenyl or naphthyl, 'heteroaryl is pyridyl, furyl, thienyl, thiazolyl, imidazolyl or oxo, and halogen It is fluorine, chlorine, bromine or iodine. Previously printed by the Intellectual Property Cooperative Employee Cooperative of the Ministry of Technology and Economy in patent applications WO 00/1 5609, WO 0 1/64633, WO 00/64634, and WO 99/0 145 1, the general formula (la) or ( lb) nitrogen nozzle derivatives and applications thereof, and in particular, these nitrogen nozzle derivatives are particularly useful because of their high affinity for cannabinol receptors and especially CB1-type receptors. Unfortunately, nitrogen-blocking derivatives The product is only very slightly water-soluble. Until now, it has been used as a nitrogen nozzle derivative of the general formula (la) or (lb), especially via the oral route in tablets containing especially cellulose, lactose and other excipients. This paper applies the Chinese National Standard (CNS) A4 specifications (210X297 quilting 200 200301108 A7 B7 V. Description of the invention (2) Modifier preparations, but not all of these preparations are suitable for these products that are hardly water soluble. Because the bioavailability is too low. (Please read the notes on the back before filling out this page.) Many documents have revealed suitable systems for dissolving hydrophobic active ingredients and / or enhancing bioavailability. However, the tested systems have so far proved to be non-existent. It is used to prepare a pharmaceutical composition containing the above-defined nitrogen-blocking derivative, which is stable and bioavailable and in which the nitrogen nozzle derivative is dissolved at an effective concentration. Specifically, J. Pharm Sciences, 89 (8), 967 (2000) and Pharmaceutical Technology Europe, ρ · 20, Setember 2000 mention the preparation of a medium-chain triglyceride with almost water-insoluble active ingredients, but tests conducted with Miglyol ® as the matrix preparation The view of bioavailability has resulted in inadequate function. Printed by the Intellectual Property of the Ministry of Economic Affairs and printed by the Consumers' Cooperative. Furthermore, the international patent application WO 95/24893 discloses the use of ingredients to modulate hydrophobic active ingredients and to enhance their bioavailability. The composition of digestible oils, lipophilic surfactants and hydrophilic surfactants, unfortunately, the above-mentioned nitrogen nozzle derivatives have proved that the bioavailability of such a preparation is too weak, specifically, this nitrogen The preparation of the mouth derivatives is also proved to be insufficient in vivo from the perspective of pharmacokinetics in the Miglyol ® / Caprylol © / Cremophor ® system. SUMMARY OF THE INVENTION And it forms the subject of the present invention, and can prepare chemically and physically stable pharmaceutical compositions, which contain derivatives of the general formula (la) or (lb), and if necessary, can be combined with another to strengthen the general formula (la) or (lb) The active ingredient of the nitrogen nozzle derivative effect, the system contains at most 2 main excipients selected from the hydrophilic paper. The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 200301108 A7 B7 V. Invention Note (3) (Please read the precautions on the back before filling in this page) Features Non-ionic surfactants that can dissolve azatan derivatives of general formula (la) or (lb), and can be used to strengthen the nitrogen nozzle if necessary Derivative effect and an active ingredient that can cause the formation of colloidal systems, a second excipient that replenishes the lipophilic nature and stabilizes the formulation as needed. According to the present invention, the preferred composition contains: • at least one active ingredient of the general formula (la) or (lb), • optionally combined with another nitrogen nozzle derivative of the general formula (la) or (lb) to enhance the effect Active ingredients, • Non-ionic surfactants with hydrophilic characteristics that can dissolve nitrogen nozzle derivatives of the general formula (la) or (lb), and if necessary, can be used to enhance the effect of nitrogen nozzle derivatives and cause colloidal system formation Active ingredients: • Select surfactants with lipophilic characteristics and HBL below 10 and stabilize the composition as needed; • Select additional additives as needed, which are selected from stabilizers, preservatives, agents that can adjust viscosity, Drugs that can improve, for example, special sensory properties, are printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, according to the present invention, and have non-ionic surfactants with hydrophilic characteristics that can dissolve nitrogen-blocking derivatives of general formula (la) or (lb). And if necessary, active ingredients that can enhance the effect of nitrogen nozzle derivatives and can cause the formation of colloidal systems can be selected from solid or semi-solid medicaments that are melted at low temperature (T ° C < 60 ° C), or optional Liquid agents ranging from 10 to 20 HLB, such as glycerides of polyethylene glycol and saturated fatty acids. Of course, in the above definition, saturated fatty acids can contain from 6 to 18 carbon atoms' and the glyceride of polyethylene glycol (PEG) and saturated fatty acids can be obtained. This paper is applicable to Chinese National Standard (CNS) A4 Specifications (2U) X 297 public love) -8-200301108 A7 _ B7 V. Description of the invention (4) Natural or synthetic. (Please read the notes on the back before filling this page.) For example, non-ionic surfactants with hydrophilic characteristics can be selected from pharmaceuticals such as Labrasol ® [hexamethylene glycol macrogol-8 glyceride] and Gelucire ® products : Gelucire 44/14, Gelucire 50/13 [lauryl (or stearyl, palmityl) macrogol-32 glyceride]. According to a preferred embodiment of the present invention, the composition may also contain a surfactant having a lipophilic characteristic and having an HBL of less than 10 and capable of stabilizing the composition. The agent may be selected from the group consisting of the formula (la) or (lb) ) Nitrogen Tsui derivative and the active ingredient related to solubility as required, according to the present invention, this agent can be selected from the group consisting of polyethylene glycol and fatty acids, especially glycerides of unsaturated fatty acids, from polyethylene glycol and fatty acids Esters or fatty acids and sorbitol esters, of course, the above fatty acids may contain from 6 to 18 carbon atoms. For example, the agent can be selected from oleic acid, Labrafil® products [oleyl (or linoleyl) macrogol-8 glyceride] such as Labrafil M1 944CS, Caprylol® (polyethylene glycol monocaprylate), or Span20 ® (sorbitan monolaurate), this list is not limited. Among the above-mentioned excipients, Labrasol ®, Gelucire ® or Labrafil ® / Labrasol ® are particularly preferred. Printed by the Consumer Goods Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (but not announced before the filing of this application). For some treatments such as obesity, it is beneficial to use nitrogen in the general formula (la) or (lb). Simultaneous use of sibutamide (sib ut am nene) when blocking derivatives' It causes a synergistic effect when reducing food consumption. Cibutramine and its effects have been revealed in the following literatures: WO 90/061 1 10; DH RYAN et al., Obesity Research, 3 (4), 5 53 (1 995); H. This paper size applies to Chinese national standards (CNS) A4 specification (2 丨 0x 297 mm) 200301108 A7 B7 V. Description of the invention (5) (Please read the notes on the back before filling this page) C. JACKSON et al., British Journal of Pharmacology, 121, 1 758 (1 997); G. FANGHANEL et al., Inter. J. Obes, 24 (2), 144 (2000); GA BRAY et al., Obes. Res., 7 (2), 189 (1 999). Moreover, for other treatments, such as schizophrenia or neurological disorders, such as Parkinson's disease, it is beneficial to use one or more of the activating agents simultaneously with the nitrogen nozzle derivative of the general formula 0a) or (lb) Agents for dopaminergic neurotransmission in the brain. These compositions can enhance the effects of dopaminergic treatment alone (levodopa, dopaminergic stimulants and inhibitors of enzymes), and reduce side effects, especially difficulty in movement. Among the dopaminergic stimulants, the products that can be specifically exemplified are as follows: Novartis, Cabergoline (Pharmacia Corp.), adrogolide (Abbott Laboratories), BAM-1 1 1 0 (Maruko Seiyaku Co Ltd), Duodopa ® (Neopharma), L-Dopa, dopadose (Neopharma), CHF1512 (Chiesi), NeuroCell-PD (Diacrin Inc), PNU-95666 (Pharmacia & Economy Printed by the Ministry of Intellectual Property Bureau's Consumer Cooperative
Upjohn)、羅比尼洛（ropinirole) (GlaxoSmithKline Beecham) 、普瑞米洛（pramipexole) (Boehringer Ingelheim)、洛帝格 丁（rotigotine) (Discovery Therapeutics, Lohmann Therapie System)、斯普安（spheramine) (Titan Pharmaceuticals)、 TV 1 203 (Teva pharmaceutical)、尿替（Polifarma)。 該組成物除了通式（la)或（lb)之氮咀衍生物及可強化其 效應之活性成份以外，當然可含上段定義之產品且該組成 物落在本發明之範圍內。 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐) -10 - 200301108 A7 _B7________ 五、發明説明（6 ) (請先閱讀背面之注意事項再填寫本頁) 根據本發明，通式（la)或（lb)之活性成份代表從〇.〇1至 7 0重量％之總組成物，其較宜代表從〇. 〇 5至5 0重量％， 且更宜代表從〇. 1至20重量％之總組成物。 給藥量當然可根據治療情形之程度或本質改變，據此 ，根據本發明組成物中的活性產物量將決定使得可以開處 方合適的給藥量，因此，通式（la)或（lb)之氮咀衍生物之量 是隨著其在混合物中的溶解度函數及用於治療病人的適當 給藥量函數而變化。 在人類中，經由口服途徑之每日用藥量通常是介於0.1 及1〇〇毫克通式（la)或（lb)之氮咀衍生物，當然選擇最合適 的給藥量必須考慮病人體重、一般身體狀態、年齡及影響 治療功效之全部因子，組成物較宜製備成含從0.1至50毫 克活性產物之單元劑量。 在通式（la)或（lb)之氮咀衍生物中，下列產品特別較佳 • 1-[雙（4-氯-苯基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基） 亞甲基]氮卩旦； 經濟部智慧財產局員工消費合作社印製 • Ν-{1·[雙（4-氯-苯基）甲基]氮咀-3-基}-1吡啶-3-基甲 基磺醯胺； • Ν-{ 1-[雙（4-氯-苯基）甲基]氮咀_3_基卜Ν-(3,5-二氟苯 基）甲基磺醯胺； • 1-[雙（4-氯-苯基）甲基]氮咀-3·基卜ν_(6-氯吡啶- 2 -基）甲基磺醯胺； • Ν-{ 1-[雙（4-氯-苯基）甲基]氮阻_3_基卜Ν_咱啉-基甲 本纸張尺度家標準（CNS )八4規格（21〇χ 297公梦）~- - ' -1：!- 200301108 A7 B7 五、發明説明（7 ) 基磺醯胺。 含這些產品之根據本發明的組成物當然特別較佳。 (請先閱讀背面之注意事項再填寫本頁) 或者是，當加入第二種活性成份時，組成物可含0.2至 50毫克在相關的產品是西布特安之情形，但是此量可視需 要下降且可在〇.2至10毫克之間變化。 在相關的產品是d-多巴之情形，組成物可含1 〇〇至 3 00毫克此第二種活性成份，較宜是250毫克。 具有親水性特徵且可造成膠體系統形成之非離子性表 面活性劑可代表從20至1 00%相對於組成物中存在的賦形 劑總重量，較宜從4 0至1 〇 〇 %且更宜從6 0至1 0 0 %。 當組成物視需要也含親脂性本質且HLB低於1 0脂藥 劑時，此低HLB藥劑之量代表從〇. i至60%相對於組成物 中存在的賦形劑總重量，且更宜從1至4 0 %。 當組成物還含額外的添加劑時，後者可以是安定劑、 防腐劑、可以調節黏度之藥劑、可以改良例如特殊感覺性 質之藥劑。 經濟部智慧財產局員工消費合作社印製 安定劑可以是例如抗氧化劑選自特別是例如從^ —生育 素、棕櫚酸抗壞血酸酯、ΒΗΤ (丁基羥基甲苯）、ΒΗΑ (丁基 羥基茴香醚）、沒食子、或蘋果酸。 舉例而言’防腐劑可以選自焦亞硫酸鈉、丙二醇、乙 醇或甘油。 在可以調節黏度之藥劑中，可以舉例的是卵磷脂、磷 脂體、丙二醇藻酸酯、藻酸鈉或甘油。 在可以改良例如特殊感覺性質之藥劑中，可以舉例的 本紙张尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） -12- 經濟部智慧財產局員工消費合作社印製 200301108 A7 ___ B7 五、發明説明（8 ) 蘋果酸、富馬酸、甘油、香草或甘露醇。 當使用此添加劑時，後者可構成從0.001%至5%之總 組成物重量。 根據本發明，醫藥組成物可得自混合視需要選用的主 要賦形劑（在固體或半固體賦形劑之情形，視需要加熱後進 行），且隨後視需要混合額外的添加劑，隨後加入通式（Ia) 或（lb)之氮咀衍生物及視需要可加強通式（Ia)或（Ib)之氮咀 衍生物效應之活性成份，且維持攪拌使得到均勻的混合物 〇 此方法之用途更詳細說明於下列實例。 根據本發明之組成物可以提供成液體、固體或半糊漿 狀態。 其特別合適存在爲硬質明膠膠囊劑或軟質明膠膠囊劑 之形式或口服溶液之形式。 根據本發明之組成物特別有利是因爲其有良好的安定 性，包括物理性及化學性，及加強的生物利用度，其可提 供口服用藥通式（la)或（lb)之氮咀衍生物。 特別較佳的組成物含： •至少一種通式（la)或（lb)之活性成份， •具有親水性特徵可溶解通式（la)或（lb)之氮咀衍生物 且可造成膠體系統形成之非離子性表面活性劑， •視需要選用具有親脂性特徵且HBL低於1 〇並能安 定組成物之表面活性劑， •視需要選用額外添加劑，其係選自安定劑、防腐劑 本纸張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） „---訂------ (請先閱讀背面之注意事項再填寫本頁) -13- 200301108 A7 B7 五、發明説明（9 ) 、可以調節黏度之藥劑、可以改良例如特殊感覺性質之藥 劑。 (請先閱讀背面之注意事項再填寫本頁) 根據本發明之另一個替代方案，較佳的組成物是定義 如上，含至少一種通式（la)或（lb)之活性成份，可以在可力D 強通式（la)或（lb)之氮阻衍生物效應之活性成份用藥前、同 時或用藥後用藥。 當然一方面含上述定義根據本發明之較佳組成物且另 一方面含可加強通式（la)或（lb)之氮咀衍生物效應之活性成 份組成物之製劑套組也落在本發明之範圍內，當然製劑套 組含可加強通式（la)或（lb)之氮咀衍生物效應之組成物、含 西布特安或含可活化腦中多巴胺能神經傳遞的藥劑之組成 物。 實施方式 提供下列非限制性實例說明根據本發明之組成物。 實例1 經濟部智慧財產局員工消費合作社印製 在室溫（2〇°C)下經由磁性攪拌在燒杯中的 M.4克 Labrasol 及 9·6 克 Labrafil M1 944CS 經 15 分鐘製備 60/40 (m/m)比例之Labrasol/Labrafil M1 944CS混合物，觀察到非 常好的互溶性，在另一個燒杯中加入200毫克1-[雙（4_氯_ 苯基）甲基；l·3· [(3, 5-二氟苯基）（甲磺醯基）亞甲基]氮咀並用 Labrasol/Labrafil M1 944CS 60/40 混合物調整成 20 克使得 到最後濃度是10毫克/克之1_[雙（4-氯-苯基）甲基]-3-[(3,5- 本紙張尺度適用中國國家標準（CNS ) A4規格ί 210X 297公釐） -14· 200301108 A7 ___B7 五、發明説明（10) (請先閱讀背面之注意事項再填寫本頁) 二氟苯基）（甲磺醯基）亞甲基]氮咀，將3成份之混合物在室 溫持續機械攪拌（3〇〇 rpm)經2小時使得到完全溶解1-[雙 (4-氯-苯基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀 ，將所得的溶液在1克份量下分配至密封的玻璃瓿並在5°C 儲存。 在5 °C經1個月顯現滿意的化學及物理安定性。 與1-[雙（4-氯-苯基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基） 亞甲基]氮咀在Miglyol ®之組成物比較，觀察到的藥物動 力學參數強化率至少是2.5。 實例2 經濟部智慧財產苟員工消費合作社印踅 經由進行上述實例1之步驟，但是起始用16.8克 Labrasol 及 7.2 克 Labrafil M1 944CS 使製造 70/3 0 (m/m)比 例之Labrasol/Labrafil M1944CS混合物，製備含200毫克 1-[雙（4-氯-苯基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基）亞甲基 ]氮咀之組成物用Labrasol/Labrafil M1 944CS 70/3 0混合物 調整成20克使得到最後濃度是10毫克/克之1-[雙（4-氯-苯 基）甲基]_3-[(3，5-二氟苯基）（甲磺醯基）亞甲基]氮咀。 在5 °C經1個月顯現滿意的化學及物理安定性。 與實例1之組成物比較，在試管內模式測試此組成物 ，將4〇〇毫克組成物在20毫升中度刺激胃液（見USP)培養 ，在3 7 °C經2小時之培養後，在2公分濾紙上過濾後進行 HPLC測試，以便測定調製物之膠體安定性。 此組成物之表現相當於實例1組成物之表現。 紙&尺度適用中國國家標準（CNS ) A4規格（2】0X29?公釐） -15- 200301108 A7 B7 五、發明説明（11 ) 實例3 (請先閱讀背面之注意事項再填寫本頁) 經由進行上述實例1之步驟，但是起始用19.2克 Labrasol 及 4.8 克 Labrafil M1 944CS 使製造 80/20 (m/m)比 例之Labrasol/Labrafil M1944CS混合物，製備含200毫克 1-[雙（4-氯-苯基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基）亞甲基 ]氮阻之組成物用Labrasol/Labrafil M1 944CS 80/20混合物 調整成20克使得到最後濃度是10毫克/克之1-[雙（4-氯-苯 基）甲基]_3-[(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀。 在5 °C經1個月顯現滿意的化學及物理安定性。 與實例1之組成物比較，在試管內模式測試此組成物 ，將400毫克組成物在20毫升中度刺激胃液（見USP)培養 ，在3 7°C經2小時之培養後，在2公分濾紙上過濾後進行 HPLC測試，以便測定調製物之膠體安定性。 此組成物之表現相當於實例1組成物之表現。 實例4 經濟部智慧財產苟β (工消費合作杜印製 經由進行上述實例1之步驟，但是起始用21.6克 Labrasol 及 2.4 克 Labrafil M1 944CS 使製造 90/10 (m/m)比 例之Labrasol/Labrafil M1 944CS混合物，製備含200毫克 1-[雙（4-氯·苯基）甲基]_3_[(3,5_二氟苯基）（甲磺醯基）亞甲基 ]氮咀之組成物用Labrasol/Labrafil M 1 944CS 90/10混合物 調整成2〇克使得到最後濃度是1〇毫克/克之1-[雙（‘氯-苯 基）甲基]-3_[(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀。 在5 °C經1個月顯現滿意的化學及物理安定性。 本紙张尺度適用中國國家標準（CMS ) Α4規格（210Χ 297公釐） -16- 200301108 A7 B7 五、發明説明（12) (請先閱讀背面之注意事項再填寫本頁) 與實例1之組成物比較，在試管內模式測試此組成物 ，將400毫克組成物在20毫升中度刺激胃液（見USP)培養 ，在3 7°C經2小時之培養後，在2公分濾紙上過濾後進行 HPLC測試，以便測定調製物之膠體安定性。 此組成物之表現相當於實例1組成物之表現。 實例5 經由進行上述實例1之步驟，但是起始只用24克 Labrasol，製備含200毫克1-[雙（4-氯-苯基）甲基]-3-[(3,5- 二氟苯基）（甲磺醯基）亞甲基]氮咀之組成物用Labrasol調整 成20克使得到最後濃度是10毫克/克之1-[雙（4-氯-苯基） 曱基]-3-[(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀。 在5 °C經1個月顯現滿意的化學及物理安定性。 與實例1之組成物比較，在試管內模式測試此組成物 ，將400毫克組成物在20毫升中度刺激胃液（見USP)培養 ，在3 7°C經2小時之培養後，在2公分濾紙上過濾後進行 HPLC測試，以便測定調製物之膠體安定性。 此組成物之表現相當於實例1組成物之表現。 經濟部智慧財產局員工消費合作社印製 實例6 經由進行上述實例1之步驟，但是起始用24克 Gelucire 44/14 取代 Labrasol/Labrafil M1 944CS 混合物，將 Gelucire 44/14事先在55°C之範圍熔化，將200毫克1-[雙 (4-氯-苯基）甲基]_3_[(3, 5-二氟苯基）（甲磺醯基）亞甲基]氮咀 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -17- 200301108 A7 B7 五、發明説明（13) 加入燒杯並用Gelucire 44/14調整成20克使得到最後濃度 是10毫克/克之1-[雙（4-氯-苯基）甲基]-3-[(3,5-二氟苯基）( 甲磺醯基）亞甲基]氮咀，將2成份之混合物在50-5 5 t持續 機械攪拌（300 rpm)經1小時使得到完全溶解1-[雙（4-氯-苯 基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀，將此 物質分配至硬質明膠膠囊內並在-2(TC之冰箱儲存過夜，然 後使用切割器將硬質明膠膠囊劑之封套與內部所含的固體 物質分離，將樣本儲存在密封的玻璃瓿並在5°C儲存。 在5 °C經1個月顯現滿意的化學及物理安定性。 與實例1之組成物比較，在試管內模式測試此組成物 ，將400毫克組成物在20毫升中度刺激胃液（見USP)培養 ，在3 7°C經2小時之培養後，在2公分濾紙上過濾後進行 HPLC測試，以便測定調製物之膠體安定性。 此組成物之表現相當於實例1組成物之表現。 實例7 在室溫（20 °C )下經由磁性攪拌在燒杯中的 3 0克 Labrasol 及 20 克 Labrafil M1 944CS 經 15 分鐘製備 60/40 (m/m)比例之Labrasol/Labrafil M1944CS混合物，觀察到非 常好的互溶性，在10毫升刻度燒杯中加入20毫克1-[雙（4-氯-苯基）甲基]-3-[(3，5·二氟苯基）（甲磺醯基）亞甲基]氮咀， 用所需量之Labrasol/Labrafil M1 944CS 60/40混合物調整 成10毫升後，將3成份之混合物在室溫持續機械攪拌（5 0 0 rpm)經2小時使得到完全溶解1-[雙（4-氯-苯基）甲基]-3- 本纸張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐) — -18- --------- (請先閱讀背面之注意事項再填寫本頁)Upjohn), ropinirole (GlaxoSmithKline Beecham), pramipexole (Boehringer Ingelheim), rotigotine (Discovery Therapeutics, Lohmann Therapie System), spheramine ( Titan Pharmaceuticals), TV 1 203 (Teva pharmaceutical), Polifarma. In addition to the nitrogen nozzle derivative of the general formula (la) or (lb) and the active ingredient that can enhance its effect, the composition may of course contain the product defined in the previous paragraph and the composition falls within the scope of the present invention. This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) -10-200301108 A7 _B7________ V. Description of the invention (6) (Please read the precautions on the back before filling this page) According to the present invention, The active ingredient of formula (la) or (lb) represents the total composition from 0.001 to 70% by weight, which more preferably represents from 0.05 to 50% by weight, and more preferably represents from 0.1 To 20% by weight of the total composition. The dosage may of course vary depending on the extent or nature of the therapeutic situation, and accordingly, the amount of active product in the composition according to the invention will determine the appropriate dosage to be prescribed. Therefore, the general formula (la) or (lb) The amount of the nitrogen nozzle derivative will vary as a function of its solubility in the mixture and of a suitable dosage for use in treating a patient. In humans, the daily dosage via the oral route is usually between 0.1 and 100 mg of a nitrogen nozzle derivative of the general formula (la) or (lb). Of course, the selection of the most appropriate dosage must take into account the patient's weight, For general physical condition, age and all factors affecting therapeutic efficacy, the composition is preferably prepared as a unit dose containing from 0.1 to 50 mg of active product. Among the nitrogen nozzle derivatives of the general formula (la) or (lb), the following products are particularly preferred • 1- [bis (4-chloro-phenyl) methyl] -3-[(3,5-difluorobenzene (Methanesulfonyl) methylene] azepine; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs • Ν- {1 · [bis (4-chloro-phenyl) methyl] nitrogen-3- } -1pyridin-3-ylmethylsulfonamide; • Ν- {1- [bis (4-chloro-phenyl) methyl] nitrogen_3_ylbN- (3,5-difluoro Phenyl) methanesulfonamide; • 1- [bis (4-chloro-phenyl) methyl] nitrogen-3.kib ν_ (6-chloropyridin-2-yl) methanesulfonamide; • Ν- {1- [bis (4-chloro-phenyl) methyl] nitrogen barrier_3_ 基卜 N_zanline-based methyl paper home standard (CNS) 8 4 specifications (21〇χ 297 public Dream) ~--'-1:!-200301108 A7 B7 V. Description of the invention (7) Sulfonamide. Compositions according to the invention containing these products are of course particularly preferred. (Please read the notes on the back before filling this page) Or, when the second active ingredient is added, the composition may contain 0.2 to 50 mg. In the case where the related product is Cibutan, but this amount can be reduced as required And can vary between 0.2 to 10 mg. In the case where the relevant product is d-dopa, the composition may contain from 100 to 300 mg of this second active ingredient, preferably 250 mg. Non-ionic surfactants that have hydrophilic characteristics and can cause the formation of colloidal systems can represent from 20 to 100% relative to the total weight of excipients present in the composition, preferably from 40 to 100% and more It should be from 60 to 100%. When the composition also contains a lipophilic nature as required and the HLB is less than 10 lipid agents, the amount of this low HLB agent represents from 0.1 to 60% relative to the total weight of the excipients present in the composition, and is more suitable. From 1 to 40%. When the composition also contains additional additives, the latter may be stabilizers, preservatives, medicaments for adjusting viscosity, medicaments for improving, for example, special sensory properties. The stabilizers printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs may be, for example, an antioxidant selected from, for example, from tocopherol, ascorbyl palmitate, butyl hydroxytoluene, butyl hydroxyanisole, Gallic, or malic acid. For example, the ' preservative may be selected from sodium metabisulfite, propylene glycol, ethanol, or glycerol. Among the agents whose viscosity can be adjusted, for example, lecithin, phosphosomes, propylene glycol alginate, sodium alginate or glycerol can be exemplified. Among the medicines that can improve, for example, special sensory properties, the paper size that can be used is exemplified by the Chinese National Standard (CNS) A4 specification (210X 297 mm) -12- Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 200301108 A7 ___ B7 5 2. Description of the invention (8) Malic acid, fumaric acid, glycerin, vanilla or mannitol. When this additive is used, the latter may constitute a total composition weight from 0.001% to 5%. According to the present invention, the pharmaceutical composition can be obtained by mixing the main excipients selected as needed (in the case of solid or semi-solid excipients, if necessary, after heating), and then mixing additional additives as needed, and then adding Nitrogen nozzle derivatives of formula (Ia) or (lb) and active ingredients that can enhance the effect of nitrogen nozzle derivatives of general formula (Ia) or (Ib) if necessary, and maintain stirring to obtain a homogeneous mixture. Uses of this method This is explained in more detail in the following examples. The composition according to the present invention may be provided in a liquid, solid or semi-slurry state. It is particularly suitably present in the form of a hard gelatin capsule or a soft gelatin capsule or an oral solution. The composition according to the present invention is particularly advantageous because it has good stability, including physical and chemical properties, and enhanced bioavailability, and can provide nitrogen nozzle derivatives of general formula (la) or (lb) for oral administration. . A particularly preferred composition contains: • at least one active ingredient of the general formula (la) or (lb), • has a hydrophilic characteristic that can dissolve nitrogen nozzle derivatives of the general formula (la) or (lb) and can cause a colloidal system The formed non-ionic surfactants, if necessary, use surfactants with lipophilic characteristics and HBL below 10 and can stabilize the composition, and select additional additives as needed, which are selected from stabilizers and preservatives. Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) ―--- Order ------ (Please read the precautions on the back before filling this page) -13- 200301108 A7 B7 V. Description of the invention (9), medicines that can adjust viscosity, medicines that can improve, for example, special sensory properties. (Please read the notes on the back before filling this page) According to another alternative of the present invention, the preferred composition is a definition As above, the active ingredient containing at least one general formula (la) or (lb) can be administered before, at the same time as, or after the active ingredient with strong nitrogen-blocking derivative effects of general formula (la) or (lb). On the one hand, of course Formulation sets according to the preferred composition of the present invention and on the other hand an active ingredient composition that enhances the effect of the nitrogen nozzle derivative of the general formula (la) or (lb) also fall within the scope of the present invention. The kit contains a composition that enhances the effect of a nitrogen nozzle derivative of the general formula (la) or (lb), a composition containing cebutan, or a drug that activates dopaminergic neurotransmission in the brain. Embodiments provide the following non- Restrictive examples illustrate the composition according to the present invention. Example 1 M.4 grams of Labrasol and 9.6 grams of M.4 printed in a beaker at room temperature (20 ° C) by magnetic stirring at the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Labrafil M1 944CS prepared a 60/40 (m / m) ratio of Labrasol / Labrafil M1 944CS mixture in 15 minutes. Very good mutual solubility was observed. 200 mg of 1- [bis (4_chloro_benzene) was added to another beaker. Methyl); l · 3 · [(3,5-difluorophenyl) (methanesulfonyl) methylene] nitrogen nozzle and adjusted to 20 g with Labrasol / Labrafil M1 944CS 60/40 mixture to the final concentration 10 mg / g of 1_ [bis (4-chloro-phenyl) methyl] -3-[(3,5- paper Dimensions are applicable to Chinese National Standard (CNS) A4 specifications Ø 210X 297 mm) -14 · 200301108 A7 ___B7 V. Description of the invention (10) (Please read the notes on the back before filling this page) Difluorophenyl) (methanesulfonate Fluorenyl) methylene] nitrogen nozzle, the 3 component mixture is continuously mechanically stirred (300 rpm) at room temperature for 2 hours to completely dissolve 1- [bis (4-chloro-phenyl) methyl]- 3-[(3,5-difluorophenyl) (methanesulfonyl) methylene] nitrogen nozzle, the resulting solution was dispensed in a 1 gram portion into a sealed glass vial and stored at 5 ° C. Satisfactory chemical and physical stability appeared at 5 ° C for 1 month. Compared with the composition of 1- [bis (4-chloro-phenyl) methyl] -3-[(3,5-difluorophenyl) (methanesulfonyl) methylene]] nitrogen in Miglyol ®, The observed enhancement rate of pharmacokinetic parameters is at least 2.5. Example 2 The Intellectual Property of the Ministry of Economic Affairs and the Employees' Cooperatives Co., Ltd. performed the steps of Example 1 above, but started with 16.8 g of Labrasol and 7.2 g of Labrafil M1 944CS to make a 70/3 0 (m / m) ratio of Labrasol / Labrafil M1944CS Mixture to prepare a composition containing 200 mg of 1- [bis (4-chloro-phenyl) methyl] -3-[(3,5-difluorophenyl) (methanesulfonyl) methylene]] Labrasol / Labrafil M1 944CS 70/3 0 mixture was adjusted to 20 g so that the final concentration was 10 mg / g of 1- [bis (4-chloro-phenyl) methyl] _3-[(3,5-difluorobenzene Group) (methanesulfonyl) methylene] nitrogen. Satisfactory chemical and physical stability appeared at 5 ° C for 1 month. Compared with the composition of Example 1, this composition was tested in a test tube mode. 400 mg of the composition was cultured in 20 ml of moderately stimulated gastric juice (see USP). After incubation at 37 ° C for 2 hours, After filtration on a 2 cm filter paper, an HPLC test was performed to determine the colloidal stability of the preparation. The performance of this composition is equivalent to that of the composition of Example 1. Paper & scales are in accordance with Chinese National Standards (CNS) A4 specifications (2) 0X29? Mm -15- 200301108 A7 B7 V. Description of invention (11) Example 3 (Please read the precautions on the back before filling this page) The procedure of Example 1 above was carried out, but starting with 19.2 g of Labrasol and 4.8 g of Labrafil M1 944CS, a 80/20 (m / m) ratio of Labrasol / Labrafil M1944CS was prepared to prepare 200 mg of 1- [bis (4-chloro -Phenyl) methyl] -3-[(3,5-difluorophenyl) (methanesulfonyl) methylene] nitrogen-blocking composition was adjusted to 20 g with Labrasol / Labrafil M1 944CS 80/20 mixture So that the final concentration is 10 mg / g of 1- [bis (4-chloro-phenyl) methyl] _3-[(3,5-difluorophenyl) (methanesulfonyl) methylene]]. Satisfactory chemical and physical stability appeared at 5 ° C for 1 month. Compared with the composition of Example 1, the composition was tested in a test tube mode. 400 mg of the composition was cultured in 20 ml of moderately stimulated gastric juice (see USP). After 2 hours of incubation at 37 ° C, the temperature was 2 cm. After filtration on a filter paper, an HPLC test was performed to determine the colloidal stability of the preparation. The performance of this composition is equivalent to that of the composition of Example 1. Example 4 Intellectual property of the Ministry of Economic Affairs (industrial-consumption cooperation Du printed by following the steps of Example 1 above, but initially using 21.6 g of Labrasol and 2.4 g of Labrafil M1 944CS to make a 90/10 (m / m) ratio of Labrasol / Labrafil M1 944CS mixture to prepare a composition containing 200 mg of 1- [bis (4-chloro · phenyl) methyl] _3 _ [(3,5_difluorophenyl) (methanesulfonyl) methylene]] The substance was adjusted to 20 g with a Labrasol / Labrafil M 1 944CS 90/10 mixture so that the final concentration was 10 mg / g of 1- [bis ('chloro-phenyl) methyl] -3 _ [(3,5-di Fluorophenyl) (methanesulfonyl) methylene] nitrogen nozzle. Satisfactory chemical and physical stability appears at 5 ° C after 1 month. This paper size applies Chinese National Standard (CMS) A4 specification (210 × 297 mm) -16- 200301108 A7 B7 V. Description of the invention (12) (Please read the notes on the back before filling out this page) Compared with the composition of Example 1, test this composition in a test tube mode, and 400 mg of the composition Culture in 20 ml of moderately stimulated gastric juice (see USP). After 2 hours of incubation at 37 ° C, filter on 2 cm filter paper and perform HPLC. Test to determine the colloidal stability of the preparation. The performance of this composition is equivalent to the performance of the composition of Example 1. Example 5 The procedure of Example 1 above was performed, but only 24 grams of Labrasol were used to prepare 200 mg of 1- The composition of [bis (4-chloro-phenyl) methyl] -3-[(3,5-difluorophenyl) (methanesulfonyl) methylene]] was adjusted to 20 g with Labrasol so that The final concentration is 10 mg / g of 1- [bis (4-chloro-phenyl) fluorenyl] -3-[(3,5-difluorophenyl) (methanesulfonyl) methylene] nitrogen. Satisfactory chemical and physical stability at 5 ° C for 1 month. Compared with the composition of Example 1, the composition was tested in a test tube mode, and 400 mg of the composition was cultured in 20 ml of moderately stimulated gastric juice (see USP). After 2 hours of incubation at 37 ° C, HPLC test was performed after filtering on a 2 cm filter paper to determine the colloidal stability of the preparation. The performance of this composition is equivalent to that of Example 1. The wisdom of the Ministry of Economic Affairs Example 6 printed by the Property Agency's Consumer Cooperative through the steps of Example 1 above, but initially replaced Labr with 24 grams of Gelucire 44/14 asol / Labrafil M1 944CS mixture, melting Gelucire 44/14 at 55 ° C in advance, 200 mg of 1- [bis (4-chloro-phenyl) methyl] _3 _ [(3, 5-difluorophenyl ) (Methanesulfonyl) Methylene] Nitrogen Tsui This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) -17- 200301108 A7 B7 V. Description of the invention (13) Add beaker and use Gelucire 44/14 Adjust to 20 g so that the final concentration is 10 mg / g of 1- [bis (4-chloro-phenyl) methyl] -3-[(3,5-difluorophenyl) (methanesulfonyl) methylene Base] nitrogen nozzle, the 2 component mixture was continuously mechanically stirred (300 rpm) at 50-5 5 t for 1 hour to completely dissolve 1- [bis (4-chloro-phenyl) methyl] -3-[( 3,5-difluorophenyl) (methanesulfonyl) methylene] nitrogen nozzle, distribute this material into hard gelatin capsules and store in -2 (TC refrigerator overnight, then use cutter to hard gelatin capsules The envelope of the agent is separated from the solid matter contained therein, and the sample is stored in a sealed glass vial and stored at 5 ° C. Satisfactory chemical and physical stability appeared at 5 ° C for 1 month. Compared with the composition of Example 1, the composition was tested in a test tube mode. 400 mg of the composition was cultured in 20 ml of moderately stimulated gastric juice (see USP). After 2 hours of incubation at 37 ° C, the temperature was 2 cm. After filtration on a filter paper, an HPLC test was performed to determine the colloidal stability of the preparation. The performance of this composition is equivalent to that of the composition of Example 1. Example 7 Prepare a 60/40 (m / m) Labrasol / Labrafil M1944CS mixture in a 60/40 (m / m) ratio of 30 g of Labrasol and 20 g of Labrafil M1 944CS in a beaker by magnetic stirring at room temperature (20 ° C). Observe Very good miscibility, add 20 mg of 1- [bis (4-chloro-phenyl) methyl] -3-[(3,5 · difluorophenyl) (methanesulfonyl) to a 10 ml graduated beaker Methylene] nitrogen nozzle, after adjusting the required amount of Labrasol / Labrafil M1 944CS 60/40 mixture to 10 ml, continue to mechanically stir the 3 component mixture at room temperature (500 rpm) to complete to 2 Dissolved 1- [bis (4-chloro-phenyl) methyl] -3- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) — -18- -------- -(Please read the notes on the back before filling this page)
、1T 4 經濟部智慈財產¾員工消費合作社印製 200301108 A7 B7 五、發明説明（14) [(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀，將所得的溶液在 2.5毫升份量下分配至密封的玻璃瓿並在5°C儲存。 (請先閱讀背面之注意事項再填寫本頁) 使用在濃度是2毫克/毫升的1-[雙（4-氯-苯基）甲基]-3-[(3,5-二氟苯基）（甲磺醯基）亞甲基]氮咀之此調製物，在1 毫克/公斤之劑量下經由口服用藥後，在猴子進行藥物動力 學硏究，爲此將溶液在蘋果汁中稀釋成十分之一以便促進 用藥至動物，稀釋後所得的乳液物理及化學安定至少經1 小時。 實例8 在室溫（20 °C )下經由磁性攪拌在燒杯中的3 0克 Labrasol 及 20 克 Labrafil M1 944CS 經 15 分鐘製備 60/40 (m/m)比例之Labrasol/Labrafil M1944CS混合物，觀察到非 常好的互溶性，在1 0毫升刻度燒杯中加入2 0毫克N - {1 -[ 雙（4-氯-苯基）甲基]氮咀-3-基}-Ν·(3,5-二氟苯基）甲基磺醯 胺，用所需量之 Labrasol/Labrafil M 1944CS 60/40 混合物 經濟部智慧財產^M工消費合作社印繁 調整成1 0毫升後，將3成份之混合物在室溫持續機械攪拌 (500 rpm)經2小時使得到完全溶解N-{1-[雙（4-氯-苯基）甲 基]氮咀-3-基}-N-(3,5-二氟苯基）甲基磺醯胺，將所得的溶 液在2.5毫升份量下分配至密封的玻璃瓿並在5°C儲存。 使用在濃度是2毫克/毫升的N-{ 1-[雙（4-氯·苯基）甲基] 氮咀-3-基}->^( 3 5 5 -二氟苯基）甲基磺醯胺之此調製物，在！ 毫克/公斤之劑量下經由口服用藥後，在猴子進行藥物動力 學硏究’爲此將溶液在顏果汁中稀釋成十分之一以便促進 本紙張尺度適用中國國家標準（CNS ) A4規格（ΓιΟΧ 297公釐） -19- 200301108 A7 B7 五、發明説明（15) 用藥至動物，稀釋後所得的乳液物理及化學安定至少經1 小時。 (請先閲讀背面之注意事項再填寫本頁) 實例9 在室溫（20 °C )下經由磁性攪拌在燒杯中的30克 Labrasol 及 20 克 Labrafil M1944CS 經 15 分鐘製備 60/40 (m/m)比例之Labrasol/Labrafil M1944CS混合物，觀察到非 常好的互溶性，在10毫升刻度燒杯中加入20毫克Ν-{1-[ 雙（4-氯-苯基）甲基]氮咀-3-基}-Ν·吡啶-3-基甲基磺醯胺， 用所需量之Labrasol/Labrafil M1944CS 60/40混合物調整 成10毫升後，將3成份之混合物在室溫持續機械攪拌（500 rpm)經2小時使得到完全溶解N-{1-[雙（4-氯-苯基）甲基]氮 阻-3-基}-1吡啶-3-基甲基磺醯胺，將所得的溶液在2.5毫 升份量下分配至密封的玻璃瓿並在5°C儲存。 經濟部智慧財產局工消費合作杜印贤 使用在濃度是1毫克/毫升的N-{1-[雙（4-氯-苯基）甲基] 氮咀-3-基丨-N-吡啶-3-基甲基磺醯胺之此調製物，在1毫克/ 公斤之劑量下經由口服用藥後，在大鼠進行藥物動力學硏 究。 實例1 〇 經由進行上述實例9之步驟，但是起始用3 0毫克N-{1-[雙（4-氯-苯基）甲基]氮 -3-基}-N-吡啶-3-基甲基磺醯胺 ，用 Labrasol/Labrafil M1 944CS 60/40 混合物調整成 10 毫 升，製備含3毫克/毫升N-{1-[雙（4_氯-苯基）甲基]氮阻-3- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） -20- 200301108 A7 B7 _ 五、發明説明（16) 基}-N_吡啶-3-基甲基磺醯胺之溶液。 (請先閱讀背面之注意事項再填寫本頁) 使用在濃度是3毫克/毫升的Ν-{1·[雙（4-氯-苯基）甲基] 氮咀-3-基丨-N-吡啶-3-基甲基磺醯胺之此調製物，在3毫克/ 公斤之劑量下經由口服用藥後，在大鼠進行藥物動力學硏 究。 實例11 經由進行上述實例9之步驟，但是起始用50毫克Ν-{ 1-[雙（4-氯-苯基）甲基]氮咀-3-基}-Ν-吡啶-3-基甲基磺醯胺 ，用 Labrasol/Labrafil M1 944CS 60/40 混合物調整成 5 毫 升，製備含10毫克/毫升N-{1-[雙（4-氯-苯基）甲基]氮阻_3_ 基卜N-吡啶-3-基甲基磺醯胺之溶液。 使用在濃度是1〇毫克/毫升的N-{1-[雙（4-氯-苯基）甲 基]氮咀-3-基}-〜吡啶-3-基甲基磺醯胺之此調製物，在1〇 毫克/公斤之劑量下經由口服用藥後，在大鼠進行藥物動力 學硏究。 經濟部智慧財產苟貸工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（2】OX 297公釐） -21 -1T 4 Intellectual Property of the Ministry of Economy ¾ Printed by the employee consumer cooperative 200301108 A7 B7 V. Description of the invention (14) [(3,5-difluorophenyl) (methanesulfonyl) methylene]] The solution was dispensed in 2.5 ml portions into sealed glass vials and stored at 5 ° C. (Please read the notes on the back before filling this page) Use 1- [bis (4-chloro-phenyl) methyl] -3-[(3,5-difluorophenyl) at a concentration of 2 mg / ml ) (Methanesulfonyl) methylene] nitrogen nozzle, after oral administration at a dose of 1 mg / kg, pharmacokinetic studies were performed in monkeys, and the solution was diluted in apple juice to One tenth in order to promote drug application to animals, the emulsion obtained after dilution is physically and chemically stable for at least 1 hour. Example 8 Prepare a 60/40 (m / m) ratio of Labrasol / Labrafil M1944CS in a 60/40 (m / m) ratio of 30 g of Labrasol and 20 g of Labrafil M1 944CS in a beaker via magnetic stirring at room temperature (20 ° C). Observe Very good miscibility, add 20 mg of N-{1-[bis (4-chloro-phenyl) methyl] nitrogen-3-yl} -N · (3,5- Difluorophenyl) methanesulfonamide, use the required amount of Labrasol / Labrafil M 1944CS 60/40 mixture, the intellectual property of the Ministry of Economic Affairs ^ M Industrial Consumer Cooperative Co., Ltd. India Fan to adjust to 10 ml, and then mix the 3 ingredients in the room Warm continuous mechanical stirring (500 rpm) over 2 hours to completely dissolve N- {1- [bis (4-chloro-phenyl) methyl] nitrogen-3-yl} -N- (3,5-difluoro Phenyl) methanesulfonamide, the resulting solution was dispensed into sealed glass vials in 2.5 ml portions and stored at 5 ° C. Use N- {1- [bis (4-chloro · phenyl) methyl] nitrogen-3-yl}-> ^ (3 5 5 -difluorophenyl) methyl at a concentration of 2 mg / ml This blend of sulfamethoxamine is here! After oral administration at a dose of mg / kg, pharmacokinetic studies were performed in monkeys. To this end, the solution was diluted to one-tenth in the color juice in order to promote the application of the Chinese National Standard (CNS) A4 specification (ΓιΟχ) on this paper scale. 297 mm) -19- 200301108 A7 B7 V. Description of the invention (15) After the medicine is applied to animals, the physical and chemical stability of the emulsion obtained after dilution is at least 1 hour. (Please read the precautions on the back before filling this page) Example 9 Preparation of 30 g of Labrasol and 20 g of Labrafil M1944CS in a beaker by magnetic stirring at room temperature (20 ° C) 60/40 (m / m ) Ratio of Labrasol / Labrafil M1944CS mixture, very good mutual solubility was observed, 20 mg of N- {1- [bis (4-chloro-phenyl) methyl] nitrogen-3-yl was added to a 10 ml graduated beaker } -N · Pyridin-3-ylmethylsulfonamide, adjusted to 10 ml with the required amount of Labrasol / Labrafil M1944CS 60/40 mixture, and continuously mechanically stir the three-component mixture at room temperature (500 rpm). N- {1- [bis (4-chloro-phenyl) methyl] nitrogen-3-yl} -1pyridin-3-ylmethylsulfonamide was completely dissolved in 2 hours, and the resulting solution was dissolved in 2.5 Dispensed into sealed glass vials in milliliters and stored at 5 ° C. Du Yinxian, Industrial and Consumer Cooperation, Bureau of Intellectual Property, Ministry of Economic Affairs, uses N- {1- [bis (4-chloro-phenyl) methyl] nitrogen-3-yl 丨 -N-pyridine-3- at a concentration of 1 mg / ml This preparation of sulfamethoxamine was administered pharmacokinetically in rats after oral administration at a dose of 1 mg / kg. Example 10 By performing the procedure of Example 9 above, but starting with 30 mg of N- {1- [bis (4-chloro-phenyl) methyl] nitro-3-yl} -N-pyridin-3-yl Methanesulfonamide, adjusted to 10 ml with a mixture of Labrasol / Labrafil M1 944CS 60/40, to prepare 3 mg / ml N- {1- [bis (4-chloro-phenyl) methyl] nitrogen-resistant-3- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) -20- 200301108 A7 B7 _ V. Description of the invention (16) A solution of the base} -N_pyridin-3-ylmethylsulfonamide. (Please read the precautions on the back before filling out this page) Use N- {1 · [bis (4-chloro-phenyl) methyl] nitrogen-3-yl 丨 -N- at a concentration of 3 mg / ml This preparation of pyridin-3-ylmethanesulfonamide was administered pharmacokinetically in rats after oral administration at a dose of 3 mg / kg. Example 11 Following the procedure of Example 9 above, but starting with 50 mg of N- {1- [bis (4-chloro-phenyl) methyl] azepine-3-yl} -N-pyridin-3-ylformyl Sulfasulfonamide, adjusted to 5 ml with a Labrasol / Labrafil M1 944CS 60/40 mixture, to prepare 10 mg / ml N- {1- [bis (4-chloro-phenyl) methyl] nitrogen block _3_ gab A solution of N-pyridin-3-ylmethylsulfonamide. N- {1- [bis (4-chloro-phenyl) methyl] nitrogen-3-yl}-~ pyridin-3-ylmethylsulfonamide was prepared at a concentration of 10 mg / ml. After oral administration at a dose of 10 mg / kg, pharmacokinetic studies were performed in rats. Printed by the Intellectual Property Cooperative of the Ministry of Economic Affairs and Consumer Cooperatives. The paper size applies to the Chinese National Standard (CNS) A4 specification (2) OX 297 mm. -21-